Voltage-gated sodium channels in nociceptive neurons are attractive targets for novel pain therapeutics. Although drugs that
target voltage-gated sodium channels have proven value as pain therapeutics, the drugs that are currently available are non-specific
sodium channel inhibitors, which limit their usefulness. Recently, a selective small-molecule inhibitor of Nav1.8, a voltage-gated sodium channel isoform that participates in peripheral pain mechanisms, has been developed. This exciting
new compound shows efficacy in several animal models of pain and is anticipated to be only the first of many new isoform-specific
sodium channel blockers.

Non-steroidal anti-inflammatory drugs (NSAIDs) are inhibitors of the cyclo-oxygenase (COX)-1 and -2 activities of prostaglandin
G/H synthase-1 and -2, respectively. They have been extensively used in the treatment of prostaglandin E2–mediated chronic inflammatory diseases. Selective COX-2 inhibitors (coxibs), which were developed to provide an alternative
with reduced gastrointestinal risk for the traditional NSAIDs, have been associated with an increased incidence of major adverse
cardiovascular events. Could the targeting of microsomal prostaglandin E2 synthase (mPGES-1) lead to novel anti-inflammatory drugs with possibly reduced risks of gastrointestinal and cardiovascular
side effects?

Andrei Goga and

Christopher Benz

Anti-Oncomir Suppression of Tumor Phenotypes

MicroRNAs (miRNAs or mirs) are small, non-coding RNAs that bind specific mRNAs and decrease their translation or increase
their degradation. miRNAs may modulate the formation and maintenance of tumors by regulating oncogene and tumor suppressor
expression. For example, overexpression of a subset of miRNAs has been inversely correlated with certain tumor phenotypes,
suggesting a role in tumor suppression. Pairs of oncogenes and the corresponding miRNAs that attenuate their expression have
been recently identified. These miRNAs, or “anti-oncomirs,” can act as natural inhibitors of oncogene function, indicating
the possibility that they might be developed as novel therapeutics.

Trypanosomatid parasites cause numerous human diseases, including African sleeping sickness and Chagas disease, affecting
millions of people worldwide. There are few effective therapeutic options presently available to treat these diseases, and
new anti-trypanosomal drugs are urgent needed. The adenosine 3′,5′-monophosphate (cAMP) signaling pathway in these parasites
appears to be an attractive target for new therapeutics, as the enzymes that create and destroy cAMP are regulated differently
from their mammalian counterparts. This review briefly summarizes the current knowledge of cAMP signaling in trypanosomes
and highlights studies of enzymes in the cAMP signaling pathway that are crucial for the survival of the parasite and are,
therefore, good targets for new anti-trypanosomal drugs.

Select this article

Lawrence D. Mayer and

Andrew S. Janoff

Optimizing Combination Chemotherapy by Controlling Drug Ratios

Cancer chemotherapy treatments typically employ drug combinations in which the dose of each agent is pushed to the brink of
unacceptable toxicity; however, emerging evidence indicates that this approach may not be providing optimal efficacy due to
the manner in which drugs interact. Specifically, whereas certain ratios of combined drugs can be synergistic, other ratios
of the same agents may be antagonistic, implying that the most efficacious combinations may be those that utilize certain
agents at reduced doses. Advances in nano-scale drug delivery vehicles now enable the translation of in vitro information
on synergistic drug ratios into improved anticancer combination therapies in which the desired drug ratio can be controlled
and maintained following administration in vivo, so that synergistic effects can be exploited. This “ratiometric” approach
to combination chemotherapy opens new opportunities to enhance the combinatorial effectiveness of existing and future therapeutic
agents across a spectrum of human diseases.